Thebaine derivatives



United States Patent 3,299,072 THEBAINE DERIVATIVES James RichardBartels-Keith, Welwyn Garden City, England, assignor to Smith Kline &French Laboratories,

Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Filed Oct.4, 1963, Ser. No. 313,793 Claims priority, application Great Britain,Oct. 10, 1962,

38,444/ 62, 38,445/ 62 14 Claims. (Cl. 260-285) This invention relatesto new thebaine derivatives as well as to intermediates and processesfor preparing them. These new thebaine derivatives have been found tohave surprising pharmacodynamic activity.

It is well known that thebaine is a powerful central nervous systemstimulant, almost a convulsant, possessing very little analgeticactivity, see Morphine & Allied Drugs, Reynolds and Randall, U. ofToronto Press 1957, page 169. Thebaine is generally conceded to be aclinically useless drug because of this stimulating eifect. It is alsoknown to the art that certain morphine derivatives such as nalorphineare analgetic antagonists. I have surprisingly discovered that certainthe'baine derivatives are not central nervous system stimulants but onthe contrary are potent central nervous system depressants. Furthermore,these new compounds have analgetic and particularly analgeticantagonistic activities. The antagonistic activity of these compounds isseveral times more potent than that of nalorphine. These compounds alsohave utility as intermediates for perparing further central nervoussystem depressant compounds as will be obvious to those skilled in theart.

The thebeaine derivatives of this invention are represented, forexample, by the following structural formula:

in which R is lower alkyl of from 14 carbon atoms preferably methyl, Ris lower alkyl of from l-4 carbon atoms preferably methyl, hydrogen oran acyl residue of a phar maceutically acceptable carboxylic acid havinga maximum of 8 carbon atoms such as acetyl, propionyl, benzoyl,isonicotinoyl or preferably nicotinoyl represents an optional singlebond at the 8, 14 position and R represents an unsaturated alkane groupor a cycloalkyl group of maximum of 8 carbons. Preferably R represents:

in which R R and R represent hydrogen, methyl or chloro atoms. Thecycloaliphatic rings can also have optional methyl substituents.

This invention also includes, as well as the basic compounds of FormulaI, the N-oxide derivatives thereof and the nontoxic acid addition orquaternary ammonium salts of the thebaine and dihydrothebaine bases orthe N-oxides thereof. For exampe, the acid addition salts are those withpharmaceutically acceptable acids such as hydrochloric, imaleic,sulfuric, phosphoric, sulfamic, benzoic, salicylic, acetic, hydrobromic,ethanedisulfonic, etc. acids. The pharmaceutically acceptable quaternaryammonium salts are those with active quarternizing agents such as loweralkyl iodides, chlorides or bromides, benzyl chloride, ethylenechlorohydrin, lower alkyl sulfates, etc. These acid addition orquaternary salts of the the'baine or dihydroethbaine compounds and theN-oxides thereof are prepared by methods well known to the art such asreacting the base in an organic solvent with an equivalent amount of theacid or halide.

The preferred compounds of this invention are those represented byFormula I in which R is allyl, 3,3-dimethylallyl or cyclopropylmethyl; Ris methyl; R is methyl, hydrogen or nicotinoyl.

The compounds of this invention are generally prepared by treatment ofthe appropriate N-northebaine with an active alkyl halide in thepresence of an acid binding agent such as an alkali metal carbonate oralternatively with an alkanoyl halide to form the N-acyl intermediatefollowed by reduction to the N-substituted thebaine such as by abimetallic hydride, for example, lithium aluminum hydride. Dependingupon what substituents are desirable for R and R and whether thethebaine or dihydrothebaine derivative is desired, the N-alkylation oracylation may be carried out early in the reaction scheme wit-h suitablefurther reactions to form the desinable thebaine nuclei. These methodsof synthesis will be obvious to one skilled in the art by the followinggeneral reaction schemes coupled with the specific exemplification.

SCHEME 1 c0R' R RCCl ne so c11 0 0 o N COR LiA 1H4 3 0 3 (II-I30 o 0onThe compounds of Formula I in which R is hydrogen 10 An alternativemethod for preparing the northebaine are prepared by protecting the3-hydr0xyl group with a compounds of Formula I which is of use as astarting suitable acyl group preferably a carbarnyl group as folmaterialis as follows. This synthetic procedure is also lows: used by modifyingthe bromination-elirnination reactions SCHEME 2 N'COR' VII coa' I -CH2RLiAlH H o "b OCH RCO R 0 3 VIII IX f (XIII- XVI) by using an alreadyN-alkylated dihydron" represents dimethyl or diethylcarbarnyl. 35thebaing di l SCHEME 3 NH C0 CMe N co (Me ch 0 O O CH3O 0 II XI CO CMeCH3O OCH3 XII XIII NC0 CMe C0 CMe TsOH M93. To 2 cr co o 0x 0 (on 2 c110 0 0011 XIV XV COCF3 H C1130 0 OCH3 01-1 0 'OCH3 XVI XVII ca 0 o o cu 5It should be noted that the reaction of compound XIV withp-toluenesulfonic acid is carried out under very mild conditions toavoid side reactions with the product isolated as the N-trifiuoroacetylderivative.

A method of preparing the dihydronorthebaine starting material (XXI)follows.

esters are prepared by reaction of the compounds of Formula VII with asuitable carbamyl chloride in basic media such as in pyridine orbenzene-triethylamine. Alternatively the esters are prepared by stepwisereaction of a compound of Formula VII with carbonyl chloride then withan amine.

N-substituted dihydronormorphinones of Formula VII have beenunexpectedly found to form O-carbamate esters such as the3-O-dimethylcarbamate or die-thylcarbamate which are stable in basicsolution and therefore especially suitable for alkylation to the enolethers as may be desired. The desired compounds of Formula I are Ingeneral the desmethylthebaine intermediates of For- 35 mula VII in whichthe final desired N-substitutent has been inserted are obtained (i) byalkylation of dihydronormorphinone, (ii) by alkylation ofdihydronorcodeinone followed by demethylation of the resulting productwith pyridine hydrochloride, boron tribormide or boron trithen obtainedby reduction as described. The carbamate 40 chloride, or (iii)preferably by the following scheme:

XXVIII Here the grouping RCO is a carbamyl group, usuallydiethylcarbamyl; the relative stability of the carbamate ester grouptowards acid permits the preparation of esters of structure XXV in goodyield.

From the above description and the examples, it will be apparent that avariety of valuable intermediates have been described as part of thisinvention. For example, among these novel intermediates are thefollowing:

N (t-butoxycarbonyl dihydronorcodeinone.

N(t-butoxycarbonyl) -A -dihydronortl1ebaine.

7-bromo-N (t-butoxycarbonyl) dihydronorcodeinone dimethyl ketal.

N( t-butoxycarbonyl norcodeinone dimethyl ketal.

N( t-butoxycarbonyl) northebaine.

N- (trifluoroacetyl) northeb aine.

Northebaine.

7-bromo-N-cyclopropylmethyldihydronorcodeinone dimethyl ketal.

N-cyclopropylmethylnorcodeinone dimethyl ketal.

N- (cyclopropanecarbonyl dihydronorcodeinone.

N- (cyclopropanecarbonyl) -A -dihydrnorthebaine.

N- (benzyloxycarbonyl) dihydronorcodeinone.

N- (benzyloxycarbonyl -A -dihydronorthebaine.

A -dihydronorthebaine.

7-bromodihydronorcodeinone dimethyl ketal.

Norcodeinone diamethyl ketal.

N-allylnorcodeinone dimethyl ketal.

Acetyldihydromorphinone.

N-triethylsilyl-A -dihydronorthebaine.

O-acetyl-N-cyanodihydronormorphinone.

N- (cyclopropanecarbonyl) dihydronormorphinone.

N- (cyclopropanecarbonyl) -O (N',N-diethylcarbamyl)dihydronormorphinone.

N- (cyclopropanecarbonyl -O (N',N'-diethylcarbamyl A-dihydronororipavine.

N- (cyclobutanecarbonyl dihydronormorphinone.

N- (cyclobutanecarbonyl) -O (N',N'-diethylcarbamyl dihydronormorphinone.

N- (cyclobutanecarbonyl) -O (N',N-diethylcarbamyl) A-dihydronororipavine.

0 (N',N'-diethylcarbamyl) dihydromorphinone.

N-cyano-O (N',N'-diethylcarbamyl) dihydronormorphinone.

O (NN'-diethylcarbamyl) dihydronormorphinone.

O(N',N-diethylcarbamyl -N (3,3 -dimethylallyl dihydronormorphinone.

O (N,N'-diethylcarbamyl) -N 3,3-dimethylallyl) A -dihydronororipavine.

N( 3,3-dimethylallyl dihydronorcodeinone.

N (3, 3 -dimethylallyl) dihydronormorphinone.

The N-oxide derivatives of this invention are prepared by reacting thebase of Formula I with an excess of a peracid or 30% aqueous hydrogenperoxide, usually with gentle heating. These N-oxide derivatives formacid addition or quaternary salts as noted hereabove. The acylderivatives (Formula I, R =acyl) are prepared by reacting the compoundsof Formula I, in which R is hydrogen with an equivalent or an excess ofthe appropriate acyl chloride or anhydride usually in the presence of anacid binding agent such as pyridine or triethylaminebenzene. Thenicotinoyl esters are particularly useful.

The following examples are exemplary of the compounds and processes ofthis invention in order to teach those skilled in the art the practiceof this invention. They are not intended to restrict the scope of thisinvention thereto.

Example 1 To a solution of dihydronorcodeinone (3.80 g.) in dioxan (38ml.) are added magnesium oxide (1.075 g.) and water (38 mL). The mixtureis stirred while a solution of t-butyl azidoformate (3.82 g.) in dioxan(15 ml.) is added dropwise. When addition is complete the pale orangemixture is maintained at 4550 C. with stirring for 20 hours, then cooledin ice and filtered using a filtration aid. The filtrate is diluted withsaturated aqueous sodium chloride (50 ml.) and water (50 ml.), andextracted with ethyl acetate (3X50 ml.). The combined ethyl acetateextracts are cooled to 4 C. and washed with ice-cold 10% aqueous citricacid (4X15 ml.) followed by saturated aqueous sodium chloride (3X 10ml.), dried over magnesium sulphate, and evaporated. The residue istaken up in chloroform and the turbid solution filtered using afiltration aid. Evaporation gives a gum which is crystallized from theminimum volume of hot ethanol giving large prisms, M.P. 151.5152.5 C.,of N(t-butoxycarbonyl)dihydronorcodeinone.

Sodium (0.227 g.) is added to dry t-butanol (40 ml.) and dry methanol(0.8 ml.) and the mixture is heated under reflux in an atmosphere of drynitrogen until dissolution is complete (45 minutes). Further dryt-butanol (20 ml.) is then added and the mixture is allowed to cool toroom temperature. A solution of N(t-butoxycarbonyl)dihydronorcodeinone(3.17 g.) in dry dioxan (30 ml.) is then added dropwise with stirringunder dry nitrogen giving an almost clear yellow solution. A solution ofdimethyl sulphate (1.14 g.) in dry t-butanol (15 ml.) is then addeddropwise with stirring, after which the mixture is stirred for 1 hour atroom temperature and then for 2 hours under reflux. Finally the solventsare removed under reduced pressure and the residue stirred with 1.5%aqueous ammonium hydroxide for 10 minutes. The sticky white solid iscollected, washed with Water, and dried. The crude product (3.26 g.) isdissolved in dry benzene and subjected to chromatography on activatedalumina (53 g.; type I-I). Elution with benzene gives a foam whichcrystallizes on treatment with light petroleum (B.P. 6080 C.) giving aproduct M.P. 163- 166 C. (1.63 g.). Recrystallization from ethanol givespure N(t-butoxycarbonyl)-A -dihydronorthebaine, needles, M.P. 168-169"C.

N(t-butoxycarbonyl)-A -dihydronorthebaine (0.900 g.) is dissolved in amixture of ethanol-free chloroform (11.5 ml.) and anhydrous methanol (45ml.), and finely divided magnesium oxide (0.073 g.) is added. Themixture is cooled in an ice-bath and stirred vigorously while brominevapour (from 0.375 g. of bromine in a small flask) is drawn through themixture by means of a slow stream of dry air (dried by passage throughconcentrated sulphuric acid), using an aspirator pump. The rate additionof bromine is such that the reaction mixture remains colorlessthroughout the addition, which takes 1.5 hours. When addition iscomplete the mixture is stirred for a further 20 minutes after which theresidual magnesium oxide is removed using a filtration aid and washedwith chloroform. Evaporation of the filtrate and washings give a residuewhich solidifies when cooled in ice and rubbed with water. The solid iscollected, washed with water, and dried. The crude product (1.27 g.)dissolves rapidly in light petroleum (B.P. 6080 C.), leaving aninsoluble residue which is collected using a filtration aid and washedwith light petroleum (B.P. 60-80 C.). Evaporation of the clear filtrateand washings gives 7-bromo-N'(t 'butoxycarbonyl)dihydronorcodeinonedimethyl ketal as a white foam which gives analytically pure material onintensive drying in a vacuum.

Potassium (0.048 g.) is dissolved in dry 2-methyl-2-butanol (10 ml.)under reflux. The resulting alkoxide solution is distilled through ashort (15 cm.) Vigreux column, dry toluene being added at a ratesuflicient to keep the volume of the mixture constant. Distillation iscontinued until the distillate consists of pure toluene (as indicated bythe temperature of distillation).

The apparatus is then re-converted for reflux and a solution of7bromo-N(t-butoxycarbonyl)dihydronorcodeinone dimethyl ketal (0.306 g.)in dry toluene (5 ml.) is added to the potassium alkoxide solution andrinsed in with further toluene 10 ml.). The mixture is then heated underreflux in an atmosphere of dry nitrogen for 24 hours, after which thereaction mixture is coo-led and treated with saturated aqueous sodiumchloride (20 ml.), and the aqueous layer extracted with ethyl acetate(2X15 ml.). The combined toluene and ethyl acetate phases are washedwith saturated aqueous sodium chloride (10 ml.), dried over magnesiumsulphate, and evaporated. The resulting brown foam (0.234 g.) is takenup in methanol and the flocculent insoluble material collected usingfiltration aid and washed with methanol. Evaporation gives a residuewhich largely dissolves in light petroleum; the small amount ofinsoluble material is removed in the same manner as before, and thefiltrate and washings are evaporate-d giving N(t-butoxycarbonyl)norcodeinone dimethyl ketal as a pale orange foam.

Repetition of this prepartion on a larger scale using substantially thesame procedure (1.06 g. of the foregoing bromo-ketal, dissolved in 25ml. of dry toluene, added to an alkoxide solution, of volume 20 ml.,prepared using 0.163 g. of potasium) gives a product which is shown byspectroscopic analysis to be a mixture ofN(t-butoxycarbonyl)norcodeinone dimethyl ketal and N(t-butoxycarbonylnorthebaine.

A Soxhlet extraction apparatus is set up with toluenep-sulphonic acidmonohydrate (0.301 g.) and chloroform (500 ml.) in the boiling flask anda thimble (28x80 mm.) filled with activated calcium sulphate in theextractor. The mixture in the flask is heated under vigorous reflux for1.5 hours, after which time the contents of the thimble have removed allthe water present in the mixture.

The solution of anhydrous toluene-p-sulphonic acid so obtained is cooledto 20 C. and a solution of N(t-butoxycarbonyl)norcodeinone di-methylketal [3.40 g.; containing some N(t-butoxycarbonyDnorthebaine] inchloroform (70 ml.) is added to the stirred solution. Stirring iscontinued for a further 2 hours at 20 C. after which the solution ispoured into a mixture of 14% aqueous potassium carbonate solution (350ml.) and 10% aqueous ammonium hydroxide (100 ml.), shaken, and thechloroform layer dried over magnesium sulphate in the presence of sodiumbicarbonate and evaporated, giving a brown foam. The crude product isstirred vigorously with successive portions of light petroleum X80 ml.)and the combined extracts are evaporated giving a straw-colored foamwhich is taken up in dry benzene and subjected to chromatography onactivated alumina (160 g.; type H). Elution with benzene and evaporationof the eluates gives N(t-butoxylcarbonyl)northebaine as a paleorange-yellow foam.

A solution of anhydrous toluene-p-sulphonic acid, prepared fromtoluene-p'sulphonic acid monodydrate (2.66 g.) and ethanol freechloroform (420 ml.; containing about 1% by weight of methanol) isstirred at room temperature while N(t-butoxycarbonyl)northebaine (1.38g.) dissolved in chloroform (30 ml.) is added. Stirring is continuedwhile the mixture is heated in a water-bath to 47-50 C. during half anhour and the temperature maintained at 47-50 for a further 2.5 hours.The mixture is then cooled in ice, poured into a mixture of saturatedaqueous sodium carbonate (150 ml.) and aqueous ammonium hydroxide (50ml.), well shaken, and the chloroform layer washed with saturatedaqueous sodium carbonate (3X50 ml. dried over magnesium sulphate, andevaporated, giving a greenish-brown foam.

This product is dissolved in a mixture of ethyl acetate and ethanol-freechloroform (25 ml.; 1:1), and the solution placed in a separatory funneland treated portionwise with a mixture of trifiuoracetic anhydride (2.5ml.) and ethyl acetate (7.5 ml.), with shaking after each addition. Whenall the reagent has been added the mixture is washed with saturatedaqueous potassium bicarbonate (50+20 ml.) and then with saturatedaqueous sodium chloride (2X10 ml.), dried over magnesium sulphate, andevaporated, giving a brown foam. This product is taken up in dry benzeneand subjected to chromatography on activated alumina (150 g.; type H).Elution with benzene and evaporation of the eluate giveN(trifluoroacetyl)northebaine as a yellow oil.

N-(trifluoracetyl)northebaine (0.109 g.) is dissolved in a mixture ofacetone (3.5 ml.) and methanol (10.5 ml.) and the mixture stirred at 25C. while 2 N-sodium hydroxide (1.40 ml.) is added dropwise. Stirring iscontinued for four hours, the temperature being maintained at 2025 C.Ten percent aqueous citric acid (14 ml.) is then added slowly withcontinued stirring, and the mixture, after dilution with water (14 ml.),extracted with ether (3X20 ml.). The aqueous phase, which had ph 3, isstirred rapidly while 10 N-sodiurn hydroxide (10 ml.) is added dropwise.The mixture, which now is at pH 11, is extracted with chloroform (3x20ml.) and the combined chloroform extracts dried over magnesium sulphateand evaporated, giving northebaine as an almost colorless gum.

A solution of northebaine (0.047 .g.) in ether (2 m1.) is filtered toremove a small amount of insoluble material. The filtrate on evaporationgives a product (0.044 g.) which is redissolved in ether (7 ml.), andthe resulting solution added slowly with shaking to a solution ofsalicyclic acid (0.016 g.) in ether (2 ml.). The resulting opalescentsuspension is evaporated, with gentle warming, to about 2 ml. whereuponthe product crystallizes. The mixture is left overnight at 0 C. afterwhich the solid is collected and washed with ether giving the salicylatesalt of northebaine, M.P. 189-490 C. (decomp.). Recrystallization fromethanol gives the pure salt as crusts, M.P. 192.5-1935" C. (decomp.).

A solution of allyl bromide (0.058 g.) in ethanol (1 ml.) is added to amixture of northebaine (0.136 g.) and finely powdered sodium bicarbonate(0.057 g.). The mixture is diluted with further ehtanol (1 ml.) and isthen heated under reflux with stirring for 21 hours. The resultingmixture is diluted with methanol (3 ml.) and the solids removed andwished with methanol using a filtration aid. The filtrate and washingsare evaporated giving a brownish residue which is extracted with boilingether (2X4 ml.). The ether-insoluble residue is digested with hotbenzene (4X2 ml.) and the benzene digests filtered using a filtrationaid; the filtrate on evaporation gives a brown gum. This product isdigested with cold benzene (5x2 ml.) and the benzene digests filtered asabove, giving, on evaporation of the filtrate, a pale brown foam whichis taken up in dry benzene and subjected to chromatography on activatedalumina (2.08 g.; type H). Elution with benzene and evaporation of theeluate gives a residue (0.044 g.) which is taken up in light petroleum.A trace of whitish residue is removed using a filtration aid, and thefiltrate is evaporated giving N-allylnorthebaine as an almost colorlessgum.

A solution of N-allylnorthebaine (0.042 g.) in ether (3 ml.) is addeddropwise to a solution of salicylic acid (0.018 g.) in ether (1 ml.).The resulting solution is gently evaporated to about half bulk,whereupon the salicylate salt crystallizes out as rosettes of needles.The mixture is set aside overnight at 0 C. and the product thencollected and washed with ether, giving a solid M.P. 178179 C. Thefurther crops of material, having M.P. 181-182 C. and 178180 C.respectively (total 0.004 g.), are obtained from the mother-liquors. Thecombined material on recrystallization from ethanol gives the puresalicylate salt of N-allylnorthebaine, needles, M. P. 183.5-194 C.

Example 2 N-cyclopropylmethyl-n -dihydronorthebaine (6.00 g., preparedas in Example 3) is dissolved in anhydrous methanol (425 ml.), andfinely divided magnesium oxide (0.54 g.) is added. The mixture is cooledin an icebath and stirred vigorously while bromine vapour (from 2.78 g.of bromine in a small flask) is drawn through the mixture by means of aslow stream of dry air (dried by passage through concentrated sulphuricacid), using an aspirator pump. The rate of addition of bromine is suchthat the reaction mixture remains colorless throughout the addition,which takes 2.5 hours. When the addition is complete the mixture isstirred for a further 15 minutes, after which the residual magnesiumoxide is removed using a filtration aid and washed with methanol.Evaporation of the filtrate and washings gives a residue which isdissolved in ethyl acetate (100 ml.) and shaken with saturated aqueoussodium carbonate solution (100 ml.). The aqueous layer is extracted withfurther ethyl acetate (250 ml.+100 ml.), and the combined ethyl acetatephases are washed with saturated aqueous sodium chloride (50 ml.), driedover magnesium sulphate, and evaporated. The residue is crystallizedfrom the minimum volume of light petroleum giving prisms, M.P. 109-110C. of 7bromoN-cyclopropylmethyldihydronorcodeinone dimethyl ketal. Themother-liquors deposit further material, M.P. 106107 C. The compound ispolymorphic, and can also be obtained as massive prisms, M.P. 112-113 C.from light petroleum.

When, in the above preparation, the residue from evaporation of thereaction mixture is treated with water and collected, there is obtained7-bromo-N-cyclopropylmethyldihydronorcodeinone dimethyl ketalhemihydrobromide (0.625 g. from 0.707 g. of the starting material), fromwhich on recrystallization from ethyl acetate is obtained as prisms,M.P. 244-246 C. (decomp.), [04 -135 (c., 0.400 in chloroform).

Potassium (0.337 g.) is dissolved in dry 2-methyl-2- butanol (40 ml.)under reflux and the resulting alkoxide solution distilled through ashort (15 cm.) Vigreux column, dry toluene being added at a ratesuflicient to keep the volume of the mixture constant. This process iscontinued until the distillate consists of pure toluene (as indicated bythe temperature of distillation; about 150 ml. of toluene is required).l

The apparatus is now re-converted for reflux and a solution of7-bromo-N-cyclopropylmethyldihydronorcodeinone dimethyl ketal (2.00 g.)in dry toluene (25 ml.) is added to the potassium alkoxide solution. Themixture is then heated under reflux in an atmosphere of dry nitrogen for24 hours, after which the reaction mixture is cooled and treated withwater (25 ml.) and the aqueous layer extracted with ethyl acetate (2X25ml.). The combined toluene and ethyl acetate phases are washed withsaturated aqueous sodium chloride (2X10 ml.), dried over magnesiumsulphate, and evaporated. The brown oil so obtained is dissolved in drytetrahydrofuran (75 ml.) and the solution added to a stirred slurry tolithium aluminum hydride (1.0 g.) in dry tetrahydrofuran (60 ml.). Themixture is heated under reflux with stirring in an atmosphere of drynitrogen for 1.5 hours, and then allowed to stand overnight at roomtemperature. The resulting mixture is decomposed by dropwise additionfirst of ethyl acetate ml.) and then of water (3 ml.). The precipitateis collected using a filtration aid and washed with ethyl acetate (5X20ml.). Evaporation of the filtrate and washings gives a syrup which istaken up in methanol (5 ml.) and the insoluble material collected on afiltration aid and washed with the minimum quantity of methanol.Evaporation of the filtrate and washings gives a residue which is takenup in light petroleum and the small amount of insoluble material removedin the same manner as before. Evaporation of the filtrate and washingsgives N-cyclopropylmethylnorcodeinone dimethyl ketal as an almostcolorless, viscous syrup.

A Soxhlet extraction apparatus is set up with toluenep-sulphonic acidmonohydrate (5.95 g.) and chloroform (480 ml.) in the boiling flask anda thimble (27 100 mm.) filled with activated calcium sulphate in theextractor. The mixture in the flask is heated under vigorous reflux for2 hours, after which time the contents of the thimble have removed allthe water present in the mixture.

The solution of anhydrous toluene-p-sulphonic acid so obtained is cooledto room temperature (20-25 C.) and a solution ofN-cyclopropylmethylnorcodeinone dimethyl ketal (3.01 g.) in chloroform(15 ml.) is added with stirring. The last traces of ketal are rinsed inwith further chloroform (15 ml.). Stirring is continued while themixture is heated in a water-bath to 4750 C. during half an hour and thetemperature maintained at 47-50 C. for a further 1 hour. The mixture isthen cooled in ice, poured into a mixture of 10% aqueous ammoniumhydroxide (60 ml.) and saturated aqueous sodium hydrogen carbonate (120ml.) well shaken (whereupon the precipitate initially formed in theaqueous phase redissolves), and the chloroform layer is separated andwashed with saturated aqueous sodium hydrogen carbonate (3X70 ml.),dried over magnesium sulphate, and evaporated under reduced pressure,giving a brown foam.

This product is dissolved in absolute ethanol (20 ml.) and a solution ofsalicylic acid (1.43 g.) in absolute ethanol (10 ml.) is added dropwisewith shaking. An oily precipitate at once appears; when the oil hassettled, the clear supernatant is decanted and the residual oil washedportionwise with absolute ethanol (total 5 ml.), the washings beingcombined with the supernatant. The resulting clear solution is seededwith a crystal of N- cyclopropylmethylnorthebaine salicylate (from apreliminary small-scale preparation), and the mixture allowed to standat 0 C. for 24 hours. The bulicolored product is then collected, washedwith absolute ethanol, and dried in a vacuum to giveN-cyclopropylmethylnorthebaine salicylate, M.P. 192.5-194.5 C. (decomp.to red-brown melt). The filtrate and washings deposit further material,and after 50 hours at 0 C. there is obtained a second crop of thesalicylate, needles M.P. 193195 C. (decomp.). The combined product isdissolved in a mixture of acetone and ethanol (2:1) and the solution,after filtration, evaporated on the steam-bath with portionwise additionof ethanol until the mixture no longer contains acetone. The solution isthen concentrated to about 25 ml. and seeded, givingN-cyclopropylmethylnorthebaine salicylate as long pinkish white needles,M.P. 197198.5 C. (decomp.), [a] 102.5 (c., 0.276 in chloroform).

Example 3 Dihydronorcodeinone (21.10 g.) is dissolved in dioxan (211ml.) and treated with water (21 ml.) and anhydrous potassium carbonate(21.1 g.). To the stirred mixture is added, dropwise,cyclopropylcarbonyl chloride (14.81 g.), during a period of 45 minutes.Stirring is continued for a further 3 hours at room temperature, afterwhich the mixture is poured into water (1100 ml.). The resultingsuspension is made alkaline to pH 11 with 2 N-sodium hydroxide andextracted with chloroform (200 ml., followed by 2 portions of ml.). Thecombined chloroform extracts are washed with N-hydrochloric acid (150ml.) and with water (150 ml.) and dried over magnesium sulphate.Evaporation of the dried extracts under reduced pressure gives a palebrown viscous oil which crystallizes when rubbed with ether givingprisms of N-cyclopropylcarbonyldihydronorcodeinone (23.70 g.), M.P.140141 C. Recrystallization from ethanol-ether gives needle clusters,M.P. 143144 C. The product can also be recrystallized from ethylacetate-light petroleum or from isopropanol-ether-light petroleum.

The purified material has [a] 295 (c., 0.440 in chloroform).

Sodium (1.67 g.) is added to dry t-butanol (300 ml.) and dry methanol(4.5 ml.) and the mixture heated under reflux in an atmosphere of drynitrogen until all the metal has dissolved. The resulting mixture isallowed to cool to room temperature and further t-butanol ml.) is added.The solution so obtained is stirred (still in an atmosphere of nitrogen)while N-cyclopropylcarbonyldihydronorcodeinone (21.0 g.), dissolved indry t-butanol (250 ml.), is added in a steady stream, giving an almostclear yellow solution. A solution of dimethyl sulphate (8.3 g.) in dryt-butanol (85 ml.) is then added dropwise with stirring, after which themixture is stirred for 1 hour at room temperature and then for 2 hoursunder reflux. Finally the bulk of the solvent is removed under reducedpressure and the residue stirred for 15 minutes with dilute aqueous.ammonia (51 ml. 0.880 aqueous ammonia dilute-d to 840 ml. with water).The mixture so obtained is extracted with chloroform (400 ml. +2 100ml.). The combined chloroform extracts are washed with water, dried andevaporated. The residue is taken up in dry benzene and subjected tochromatography on activated alumina (400 g.; type H). Elution with her:-zene gives a foam which crystallizes on treatment with ether, givingN-cyclopropylcarbonyl-A -dihydron-orthebaine, M.P. 134135 C. The M.P. isunchanged on recrystallization from benzene-light petroleum To asuspension of lithium aluminum hydride (3.0 g.) in dry tetrahydrofuran(150 ml.) is added a solution of N-cyclopropylcarbonyl-A-dihydronorthebaine (6.0 g.) in dry tetrahydrofuran (225 ml.). Themixture is heated under reflux with stirring for 3 hours in anatmosphere of dry nitrogen; then the mixture is cooled in an ice bath,decomposed by the dropwise addition, with stirring, of a mixture ofethyl acetate (30 ml.) and ether 30 ml.), followed by cautious, dropwiseaddition of water (9 ml.). The gelatinous precipitate is collected using.a filtration aid and washed with ethyl acetate (300 ml.). The combinedfiltrate and washings are evaporated to dryness to give a gum (5.5 g.),a portion of which crystallizes when cooled and rubbed with lightpetroleum. The remainder of the product when dissolved in the minimumvolume (about 4 ml. per gram) of methanol and seeded with the foregingcrystalline material gives rectangular tablets or rods ofN-cyclopropylmethyl-A -dihydronorthe'baine, M.P. 112.5-113 C., 270 (c.,0.432 in chloroform).

A solution of N-cyclopropylmethyl-A -di-hydronorthebaine (2.0 g.) inmethanol (100 ml.) is cooled to 0 C. and stirred while a solutionprepared by diluting 3.734 N-hydrobromic acid (1.52 ml.) with methanol(20 ml.) is added dropwise. The resulting mixture is diluted withbenzene (50 ml.) and evaporated under reduced pressure. Further benzene(50 ml.) is added to the residue and the mixture re-evaporated. Thecrystalline residue is recrystallized from acetone-methanol (1:1) togive the hydrobromide as rods, M.P. 270272 C. (decomp.).

An aliquot of this product (500 mg.) in ethanol is reacted with anexcess of ethylenechlor-ohydrin to give the quaternary salt.

Example 4 Benzyl chloroformate (4.57 g.) is added dropwise with vigorousstirring to .a mixture of dihydronorcodeinone (5.74 g.), potassiumcarbonate (5.73 g.), and water (5.7 ml.) during a period of 30 minutes.The resulting mixture is stirred for 2 hours at room temperature andthen poured into water (300 ml.) containing 2 N-sodium hydroxide (5ml.). The resulting oily suspension is extracted with chloroform (200+2100 ml.) and the combined extracts washed with 2 N-sodium hydroxide(2X50 ml.), 2 N-sulphuric acid (2X50 ml.), Water (50 ml.), and finallywith saturated aqueous sodium bicarbonate (50 ml.), then dried overmagnesium sulphate. Evaporation of the dried extracts gives a yellowglass (9.94 g.) which is dissolved in absolute ethanol (75 ml.) to whichacetic acid (7.5 g.) has been added. To the resulting solution is addedGirards reagent P (6 g.) and the mixture is heated under reflux for 1hour. The reaction mixture is then cooled and poured into ice-water (500ml.) containing 0.5 N-sodium hydroxide (225 ml.) and the neutralsolution extracted with ether (4x 100 ml.)

The aqueous phase is treated by 6 N-suphuric acid m1.) and set aside for1 hour after which the resulting oily suspension is extracted withchloroform (3x100 ml.). The combined chloroform extracts are washed withwater (2x100 ml.), saturated aqueous sodium bicarbonate (50 ml.), andfinally again with water ml.), dried over magnesium sulphate, andevaporated. Pure N-(benzyloxycarbonyl)dihydronorcodeinone is thusobtained as a white foam.

Sodium (0.515 g.) is added to a mixture of dry methanol (1.5 ml.) anddry t-butanol (94 ml.) and the mixture heated under reflux with stirringin an atmosphere of dry nitrogen until dissolution of the metal iscomplete. The reaction mixture is then cooled to room temperature anddiluted with further dry t-butanol (47 ml.). With continued stirring andpassage of nitrogen, a solution ofN-(benzyloxycarbonyl)dihydronorcodeinone (7.85 g.) in dry t-butanol (47ml.) is added; to the yellow solution so obtained is added, dropwise, asolution of dimethyl sulphate (2.60 g.) in -dry t-butanol (23 ml).During this addition a fine precipitate appears. The mixture is stirredat room temperature for a further hour and then under reflux (stillunder nitrogen) for 2 hours. Finally the bulk of the solvent is removedunder reduced pressure and the residue is stirred with 1.5% aqueousammonium hydroxide (300 ml.) and saturated aqueous sodium chloride (50ml.), extracted with chloroform (100+2 50 ml.), and the combinedchloroform extracts washed with water ml.), dried (magnesium sulphate),and evaporated. The yellow foam (8 g.) so obtained is purified bychromatography on alumina (type H; 220 g); elution with benzene andevaporation of the eluate give pure N-(.benzyloxycarbonyl)-A-dihydronorthebaine as a white foam (4.03 g).

To N (benzyloxycarbonyl) A dihydronorthebaine (17.9 g.) is addedtriethylsilane (19.5 g), triethylamine (0.23 ml.), and paladium chloride(200 mg). The mixture is heated under reflux with stirring. After 1.5hours further triethylamine (0.13 ml.) and paladium chloride (100 mg.)are added, and heating with stirring continued for a further 2 hours.The reaction mixture is then cooled and the solids separated using afiltration aid and Washed with warm dioxan (about 20 ml.). The filtrateand washings are treated with methanol (70 ml.) and after 10 minutes themixture is poured into ice-cold 10% aqueous citric acid solution (900ml.) The mixture so obtained is extracted with ether (3 X400 ml.), andthe aqueous layer cooled in ice, made alkaline by cautious addition of50% aqueous sodium hydroxide (400 ml.), extracted with chloroform (3x250ml.), and the combined chloroform extracts washed with water, dried, andevaporated. The residue on cautious treatment with ether, followed byaddition of an equal volume of light petroleum gives a crystalline solidM.P. l48.5149.5 C. 9.7 grams of this crude product on recrystallizationfrom ethyl acetate gives A -dihydronorthebaine as large prisms, M.P.152-1525 C. A second crop M.P. 151152.5 C is obtained from themother-liquors.

A -dihydronorthebaine (6.00 g.) is dissolved in anhydrous methanol (600ml.), and finely divided magnesium oxide (0.638 g.) added. The mixtureis cooled in ice and stirred vigorously while bromine vapour (from 3.241g. of bromine) is introduced in a current of dry air by the method usedin the preparation of the N-cyclopropylmethyl analogue. After additionof the bromine, which takes 2 hours, the mixture is stirred for afurther 15 minutes at 0 C. and then for 2 hours at room temperature. Theresidual magnesium oxide is then removed using a filtration aid andwashed with methanol, and the filtrate and washings taken to dryness.The residue is treated with water (100 ml.), followed by saturatedaqueous sodium carbonate (50 ml.), and the mixture extracted withchloroform (3x100 ml.). The combined chloroform extracts are washed withwater,

dried, and evaporated, to give 7-bromodihydronorcodeinone dimethyl ketalas a white foam.

Potassium (1.41 g.) is dissolved in dry 2-methyl-2- butanol (160 ml.)under reflux and the resulting alkoxide solution distilled through a 30cm. Vigreux column, dry toluene being added at a rate sufficient to keepthe volume of the mixture constant. This process is continued until thedistillate consists of pure toluene (as is indicated by the temperatureof distillation).

The apparatus is then re-converted for reflux and a solution of7bromodihydronorcodeinone dimethyl ketal (7.40 g.) in dry toluene (50ml.) is added in one portion. The mixture is then stirred under refluxin an atmosphere of dry nitrogen for a further 23 hours, then cooled andtreated with saturated aqueous sodium chloride (100 ml.). The aqueousphase is separated and extracted with ethyl acetate (2X 100 ml.), andthe combined toluene and ethyl acetate phases washed repeatedly withsaturated aqueous sodium chloride until the aqueous washings have a pHvalue of less than 9, dried, and evaporated, giving a gum (6.1 g.). Thisproduct is taken up in methanol and a trace of flocculent materialremoved using a filtration aid and washed with methanol. Evaporation ofthe filtrate and washings and dissolution of the residue in ether gives.a solution which on dilution with light petroleum deposits a brown gum.The filtrate after removal of this gum is diluted with further lightpetroleum, seeded with pure norcodeinone dimethyl ketal (see below), andallowed to stand at C. for 3 days. Collection gives norcodeinonedimethyl ketal as gummy crystals, M.P. 99l00 C. (1.90 g.). Furthermaterial, M.P. 9l97 C. (0.89 g.) is obtained by evaporating themother-liquors to dryness and crystallizing the residue frombenzene-light petroleum; evaporation of the mother-liquors from thissecond crystallization gives a semi-crystalline residue. All thesefractions are shown by infra-red spectroscopy to consist of norcodeinonedimethyl ketal contaminated by a small proportion of northebaine whichcould not be removed by crystallization.

Pure norcodeinone dimethyl ketal is obtained from a small-scaledehydrobromination, starting from 0.207 g. of the bromo-ketal. Isolationas described above gives a gum (0.160 g.) which is crystallized from 1:1ether-light petroleum giving the pure ketal as fine cream-coloredneedles, M.P. 104-l06 C. (0.107 g.).

A mixture of norcodeinone dimethyl ketal (3.29 g.; containing a smallporportion of northebaine), finely powdered sodium bicarbonate (1.26g.), allyl bromide (1.24 g.), and absolute ethanol (40 ml.) is heatedunder reflux with stirring for 22.5 hours. The mixture is cooled and thesolids removed and washed with methanol. Evaporation of the filtrate andwashings gives a gum which largely dissolves on addition of lightpetroleum, leaving a residue which is collected using a filtration aidand washed with further light petroleum. Evaporation of the filtrate andwashings gives crude N-allylnorcodeinone dimethyl ketal (3.329 g.) as anorange oil which is used dlrectly for the next step.

A Soxhlet extraction apparatus is set up with toluene-psulphonic acid(6.80 g.) and chloroform (500 ml.) in the boiling flask and a thimble(28 x80 mm.) filled with anhydrous magnesium sulfate in the extractor.The mixture in the flask is heated under vigorous reflux for 2 hours,and then cooled to 20-25 C.

A solution of N-allylnorcodeinone dimethyl ketal (3.27 g.) in chloroform(50 ml.) is then added to the foregoing solution of anhydroustoluene-p-sulphonic acid, and the mixture stirred while the temperatureis raised to 47- 50 C. during half an hour, maintained at 4750 C. for afurther half hour, cooled in ice, and finally poured into a mixture of10% aqueous ammonium hydroxide (60 ml.) and saturated aqueous sodiumbicarbonate (150 ml.), well shaken, and the chloroform layer separated16 and washed with saturated aqueous sodium bicarbonate (3 x 70 ml.),dried, and evaporated under reduced pressure, giving a brown gum.

This product is purified by chromatography on alumina (60 g.; type H);elution with benzene and evaporation of the eluate gives a residue whichlargely dissolves on treatment with light petroleum. The insolublematerial is removed using a filtration aid and washed with lightpetroleum and the filtrate and washings evaporated givingN-allylnorthebaine base as a pale yellow syrup.

The base so obtained is dissolved in ether (10 ml.) and the solutionadded dropwise to a solution of salicylic acid (0.27 g.) in ether. Thesalicylate salt crystallizes out on seeding with a crystal from aprevious preparation, and the mixture is set aside overnight at 0 C.Collection gives the salicylate salt, M.P. 179-180 C. which ondissolution in acetone, dilution with ethanol, and removal of theacetone under reduced pressure, crystallizes as fine needles, M.P.186.5l87.5 C. of pure N-allylnorthebaine salicylate, identical (mixedM.P. and infrared spectrum) with the product obtained by alkylation ofnorthebaine.

Example 5 Dihydromorphinone base (52.33 g.), acetic acid (131 ml.), andacetic anhydride (131 ml.) are heated together under reflux for 1.25hours. The reaction mixture is then cooled in ice and treated with anexcess of saturated aqueous sodium carbonate, and the product isolatedby extraction with chloroform (3 X 150 ml.). The combined chloroformextracts are washed with 2 N-sodium hydroxide (200 ml.) and then withsaturated aqueous sodium chloride (2x200 ml.), dried (magnesiumsulphate) and evaporated. The resulting foam crystallizes on treatmentwith a mixture of light petroleum and ethyl acetate, giving prisms, M.P.121.5122.5 C. of acetyldihydromorphinone.

Acetyldihydromorphinone (50 g.), dissolved in chloroform ml.), is addedslowly with stirring during 20 minutes to a solution of cyanogen bromide(16.40 g.) in chloroform. Heat is evolved. After the initial reactionhas subsided, the mixture is heated on the water-bath for 2 hours, afterwhich the solvent is removed under reduced pressure. The residue ontreatment with hot water gives crude O acetylN-cyanodihydronormorphinone which is washed with hot water and then withcold wa ter. Recrystallization from methanol gives the purecyano-compound as yellowish prisms, M.P. 98100 C. (efferv.).

The whole of the crude cyano-compound is heated under reflux for 4 hourswith 1.66 N-hydrochloric acid, after which the mixture is allowed tostand overnight. Collection of the prisms which appear gives knowndihydronormorphinone hydrochloride, M.P. 345-350" C. (decomp.).Alternatively, the whole of the reaction mixture is warmed to 4050 C.and just sufficient water added to dissolve the solid. Aqueous ammoniumhydroxide (10%) is then added until the mixture has pH 8. Theprecipitate is collected, washed with water and dried.Dihydronormorphinone so obtained (37.23 g.) has M.P. 305-306 C.(decomp.).

Dihydronormorphinone (25 g), dioxan (250 ml.), water (25 ml.), andpotassium carbonate (25 g.) are stirred together andcyclopropanecarbonyl chloride (18 g.) added. Stirring is continued for20 hours at room temperature; then 2 N-sodium hydroxide (200 ml.) isadded and the mixture stirred for a further 45 minutes. The mixture isextracted with ethyl acetate (4x100 ml.) to remove anycyclopropanecarboxylic ester formed, and the aqueous layer adjusted topH 2 with 2 N-hydrochloric acid. Collection of the precipitate givesN-(cyclopropanecarbonyl) dihydronormorphinone, M.P. 338340 C. (decomp.).

N,N-diethylcarbamyl chloride (8 g.) is added dropwise to a solution ofN-(cyclopropanecarbonyl) dihydronor- .morphinone (10 g.) in dry pyridine(50 ml.), and the last traces 'of chloride washed in with furtherpyridine (10 ml.). The mixture is then heated under reflux with stirringfor 4 hours, during which time all the solid initially presentdissolves. The reaction mixture is cooled in ice, treated withsufficient 6 N-sulph-uric acid to remove the pyridine, and extractedwith chloroform (4X 10 ml.). The combined chloroform extracts are washedwith 2.5 N'sodium hydroxide (3x100 ml.) and with water (2x100 ml.),dried (magnesium sulphate) and evaporated, giving a brown foam.

This product is dissolved in absolute ethanol (75 ml.) containing aceticacid (7.5 g.), Girards reagent P (6 g.) added, and the mixture heatedunder reflux for 1 hour. The reaction mixture is cooled and poured intoice-water (500 ml.) containing 0.5 N-sodium hydroxide (225 ml.). Theaqueous mixture is extracted with ether (4x100 ml.), and the aqueousphase is then treated with 6 N- sulphuric acid (80 ml.) and set asidefor 1 hour. The resulting aqueous suspension is extracted with benzene(200-|-2 100 ml.), and the combined extracts are Washed with water(2x100 ml.) and with saturated aqueous sodium bicarbonate (100 ml.),dried (magnesium sulphate), and evaporated.

The residue (8.80 g.) is further purified by chromatography on alumina(type H; 150 g.); elution with benzene containing 0.3% of methanol andevaporation of the eluate give pure N (cyclopropanecarbonyl) O (N'., Ndiethylcarbamyl) dihydronormorphinone as a colorless glass whichsubsequently crystallizes as needles on treatment with benzene and thenhas M.P. 176177 C.

(previous sintering at 95100 C.).

(1) Sodium (0.363 g.) is dissolved in a mixture of dry t-butanol (92ml.) and dry methanol (1.5 ml.) with stirring under reflux in anatmosphere of nitrogen. When all the sodium has dissolved furthert-butanol (46 ml.) is added and the mixture allowed to cool to roomtemperature. A solution of N (cyclopropanecarbonyl) O- (N,N'diethylcarbamyl) dihydronormorphinone (5.75 g.) in t-butanol (46 ml.) isthen added with stirring under nitrogen, which is maintained for theremainder of the preparation. A solution of dimethyl sulphate (1.82 g.)in t-butanol (25 ml.) is then added dropwise with stirring, and themixture stirred for 1 hour at room temperature and then for 2 hoursunder reflux. The bulk of the solvent is then removed under reducedpressure and the residue stirred with 1.5% aqueous ammonium hydroxide(300 ml.), extracted with benzene (200-1-2X100 ml.), and the combinedbenzene extracts washed with saturated aqueous sodium chloride (100ml.), dried over magnesium sulphate, and evaporated. The residue (5.41g.) is purified by chromatography on alumina (150 g.; type H) andelution with benzene containing 0.1% of methanol. Evaporation of theeluate gives a foam (4.7 g.) which on crystallization from ether givesN-(cyclopropanecarbonyl) O (N,N' diethylcarbamyl) A dihydronoroipavine,needle clusters M.P. 7578 C.

(2) A solution of N (cyclopropanecarbonyl) O- (N',N diethylcarbamyl)dihydronormorphinone (8.55 g.) in dry dimethyl sulphoxide (20 ml.) isstirred in an atmosphere of dry nitrogen while a solution of sodium(methylsulphinyl)methyl in dimethyl sulphoxide (31.8 ml.; 0.632 M;prepared and standardized by the method of Corey and Chayakowski, J.Amer. Chem. Soc., 1962, 84, 866) is added, followed immediately bydropwise addition of a solution of dimethyl sulphate (2.46 g.) indimethyl sulphoxide (7 ml.), the last traces of dimethyl sulphate beingwashed in with further dimethyl sulphoxide ml.). Stirring under nitrogenis continued for a further 2 hours after which the bulk of the solventis removed in vacuo (0.5 mm.). Treatment of the reisdue with 1.5%aqueous ammonium hydroxide (100 ml.) gives a solid which is collected,washed Well with water, and dried in vacuo. This product (5.57 g.) onchromatography on alumina (120 g.; type H) and elution with benzenecontaining 10% of ethyl acetate, followed by evaporation of the eluate,gives a residue which when rubbed with light petroleum at 0 C. gives N(cyclopropanecarbonyl) 0 (N',N diethylcarbamyl) A dihydronororipavine,M.P. 7679 C. (2.82 g), identical (infra-red spectrum) with the productobtained by method (1). The product is recrystallized with difficultyfrom ethyl acetate, giving material M.P. 8384 C.

A solution of N (cyclopropanecarbonyl) O (N,N- diethylcarbamyl) Adihydronororipavine (2.82 g.) in dry tetrahydrofuran ml.) is added to astirred slurry of lithium aluminum hydride (1.41 g.) in drytetrahydrofuran (80 ml.). The mixture is stirred under reflux in anatmosphere of dry nitrogen for 3 hours, after which the mixture iscooled in ice-water and stirring continued while a mixture of ethylacetate (14 ml.) and ether (30 ml.) is added dropwise, followed bycautious addition of a solution of disodium dihydrogenethylenediaminetetraacetate (17.5 g.) in water (80 ml.). After additionof benzene (50 ml.), saturated aqueous sodium bicarbonate is added untilthe aqueous phase has pH 8. The upper phase is separated and the aqueousphase extracted with benzene (2x100 ml.). The continued upper phases aredried over magnesium sulphate and evaporated, giving crude Ncyclopropylmethyl A dihydronororipavine as a foam. A solution of thisproduct in a mixture of ethanol (2.5 ml.) and ether (25 ml.) is treatedportionwise with a solution of salicylic acid (2.50 g.) in ether (25ml.). The mixture is gently warmed on the water-bath and then left for1.4 hours at 0 C. after which collection gives the crude salicylatesalt, M.P. 222227 C. (decomp.). Recrystallization from ethanol givespure N-cyclopropylmethyl-A -dihydronoroipavine salicylate, M.P. 225-227C. (decomp.).

This material (500 mg.) is dissolved in pyridine and reacted with anexcess of nicotinoyl chloride. Quenching in water gives the nicotinoylester.

Example 6 A stirred suspension of dihydronormorphinone (30 g.) in dioxan(300ml) is cooled in ice-water and treated successively with potassiumcarbonate (30 g.), water (30 ml.), and cyclobutanecarbonyl chloride(24.2 g.). The resulting mixture is stirred for 20 hours at roomtemperature and then treated with 2 N-sodium hydroxide (180 ml.),stirred for a further 45 minutes, and finally extracted with ether (3X60ml.). The aqueous phase is cooled in ice and acidified with 6N-hydrochloric acid, and the buff colored product collected, washed withwater, and dried, giving almost pureN-cyclobutanecarbonyl)dihydronormorphinone, M.P. 285 C. (decomp.).

The foregoing ether extracts are dried and evaporated giving an orangeoil which is dissolved in a mixture of 2 N-sodium hydroxide ml.) andethanol (100 ml.) and the solution maintained at 60 C. for 1 hour in anatmosphere of nitrogen and then cooled and acidified with 6N-hydrochloric acid, giving a further crop of the product. Thismaterial, when recrystallized by dissolution in hot chloroformethanol(1:1) followed by removal of most of the chloroform, gives the pureproduct as prisms, M.P. 293 C. (decomp.), identical (infra-red spectrum)with the foregoing material.

A solution of diethylcarbamyl chloride (19.3 g.) in anhydrous pyridine(20 ml.) is added dropwise to a stirred suspension ofN-(cyclobutylcarbonyl)dihydronormorphinone (25 g.) in anhydrous pyridineml.) after which the mixture is heated under reflux for 4 hours. Theresulting pale brown solution is cooled in ice and treated withsufficient 6 N-sulph uric acid to dissolvethe pyridine, and the mixtureextracted with chloroform (+2X 100 ml.). The combined chloroformextracts are washed with 2 N-sodium hydroxide (100 ml.) and with water(100 ml.), dried, and evaporated. The residue is dissolved in theminimum volume of hot ethanol and the solution treated with ether untila faint turbidity appears; minute needle clusters appear on standing.Collection gives essentially pure N (cyclobutanecarbonyl) O-(N',N-di-1.9 ethylcarbamyl)dihydronormorphinone, M.P. 172-174 C. Further, lesspure material is obtained from the motherliquors. Furtherrecrystallization of the first crop material gives analytically purematerial M.P. 173-174 C.

The compound is prepared by the same two methods as were used for thepreparation of the corresponding N- cyclopropanecarbonyl derivative.

(1) N (cyclobutanecarbonyl) O (N,N-diethylcarbamyl)-dihydronormorphinone(2.26 g.) on methylation in the presence of sodium t-butoxide givesN-(cyclobutanecarbonyl) O-(N,N-diethylcarbamyl)A -dihydronororipavine asa gum.

(2) The same starting material (9.69 g.) on methylation in the presenceof sodium (methylsulphinyl) methyl gives the nororipavine derivativeidentical infra-red spectrum with material obtained by method (1).

N (eyclobutanecarbonyl)-O-(N,N-diethylcarbamyl)- A -dihydronororipavine(4.85 g.) is reduced with lithium aluminum hydride by the method usedfor the preparation of the corresponding N-cyclopropylmethyl derivative.Isolation gives crude N (cyclobutylmethyl)A -dihydronororipavine (4.25g.) which is converted to the salicylate salt needle-clusters M.P.231232 C. (decomp.) from ethanol. Alternatively trituration of the crudereduction product with ether gives the free base as an amorphous solidM.P. 103-104 C.

An aliquot of the base (200 mg.) in hot ethanol is heated on the steambath with ethyl iodide. Cooling and trituration gives the ethiodidequaternary. Another aliquot (200 mg.) is reacted in pyridine with anexcess of acetic anhydride. Quenching gives the acetate ester.

Another portion (500 mg.) in ethanol is mixed with an exces of aqueoushydrogen peroxide on the steam bath. Concentration and cooling gives theN-oxide derivative. This material (50 mg.) in ether is reacted with anequivalent quantity of methanolic hydrogen chloride at 0 C. to give thehydrochloride salt.

Example 7 The process of Example 1 is repeated substituting in equimolarquantities propargyl chloride for allyl bromide to giveN-propargylnorthebaine. Substituting 3,3-dimethylallyl gives N 3,3dimethylallylnorthebaine. 3,3- dichloroallyl bromide substituted inExample 4 using sodium bicarbonate in ethanol give3,3-dichloroallylnorthebaine. Substituting cyclopentylcarbonyl chlorideor cyclohexylcarbonyl chloride for the cyclopropylcarbonyl chloride ofExample 5 gives N-cyclopentylmethyl orN-cyclohexylmethyl-M-dihydronororipavine.

Example 8 A solution of dihydromorphinone base (46.0 g.) in dry pyridine(230 ml.) is stirred while diethylcarbamyl chloride (43.7 g.) is addedslowly. The resulting mixture is stirred under reflux for 3 hours, afterwhich the solvent is removed under reduced pressure. The syrupy residueis taken up in warm water (150 ml.) and the solution concentrated to 100ml. under reduced pressure, treated with charcoal at the boiling point,filtered, and the filtrate cooled and made alkaline with 10 N-sodiumhydroxide (30 ml.). The oily suspension is extracted with benzene (100+250 ml.) and the combined benzene extracts are washed with saturatedaqueous sodium chloride (50 ml.), dried over magnesium sulphate (withcharcoal), and evaporated. The resulting oil is treated with lightpetroleum (200 ml.) and left overnight at 0 C. The crystalline mass soobtained is broken up and the solid collected, washed with 1:1ether-light petroleum, and dried. The product has M.P. 122124 C.',recrystallization from ethyl acetate gives pureN,N-diethylcarbamyldihydromorphinone (35.0 g.) in chloroform 100 ml.) isadded dropwise A solution of N',N'-diethylcarbamyldihydromorphinone(35.0 g.) in chloroform 100 ml.) is added dropwise with stirring to asolution of cyanogen bromide (9.72 g.) in chloroform ml.). Heat isevolved during the addition, which takes 40 minutes. When addition iscomplete, the mixture is stirred under gentle reflux for 2 hours andthen evaporated under reduced pressure. The residue is mixed withethanol (50 ml.), and re-evaporated under reduced pressure, giving asyrup which begins to crystallize. This product solidifies completely ontreatment with warm water ml.); the solid is collected, washed with hotwater, and dried, givingN-cyano-O(N,N'-diethy1carbamyl)dihydronormorphinone, M.P. -168 C.Recrystallization from ethanol gives felted needles, M.P. 190192 C. withsintering at C.

vA mixture of N-cyano-O(N',N-diethylcarbamyl)-dihydronormorphinone (29.1g.) and 2 N-hydrochloric acid (500 ml.) is stirred under reflux for 4hours. The resulting clear yellow solution is allowed to stand overnightat room temperature, then stirred with charcoal, filtered, and thefiltrate made alkaline with 10 N-sodium hydroxide (150 ml.). The oilysuspension is extracted with ethyl acetate (3x250 ml.) and the combinedextracts washed with 2 N-sodium hydroxide (100 ml.) and with saturatedaqueous sodium chloride (100 ml.), dried over magnesium sulphate withcharcoal, and evaporated, giving O(N,N'-diethylcarbamyl)dihydronormorphinone as a cream colored foam.

A mixture of O(N',N'-diethylcarbamyl)dihydronormorphinone (2.96 g.),1-brorno-3-methyl-2-butene (1.20 g.), sodium bicarbonate (1.01 g), andN,N-dimethylformamide (25 ml.) is stirred under reflux for 5 hours. Themixture is then cooled and the solids separated using a filtration aidand washed with ethanol. The filtrate and washings on evaporation underreduced pressure give a dark brown oil which dissolves slowly onaddition of 2 N-hydrochloric acid (50 ml.) The resulting brown, turbidsolution is treated with charcoal, filtered using a filtration aid, andthe pale orange filtrate extracted with ether (3X50 ml.). The aqueousphase is made alkaline with an excess of concentrated aqueous ammoniumhydroxide and the oily suspension extracted with ether (3X25 ml.). Thecombined ethereal phases from this second extraction are dried overmagnesium sulphate with added charcoal and evaporated to giveO(N,N'-diethylcarbamyl) N(3,3 dimethylallyl)dihydronormorphinone (2.14g.) as a pale yellow foam. A portion of this product (2.03 g.) isdissovled in ethanol (10 ml.) and the solution added dropwise withshaking to a solution of (+)-tartaric acid (1.02 g.) in ethanol (10ml.), A gelatinous precipitate appears at first but redissolves onwarming; on scratching and cooling the acid tartrate appears as needles,M.P. 152-154 C. An aqueous solution of the acid tartrate (1.95 g. in 20ml.) on treatment with an excess of concentrated aqueous ammoniumhydroxide gives pureO(N',N-diethylcarbamyl)-N(3,3-dimethylallyl)dihydronormorphinone as agranular solid, M.P. 62 C. (unsharp).

O(N,N' diethylcarbamyl) N(3,3 dimethylallyl)dihydronormorphinone (5.50g.) on methylation in the presence of sodium (methylsulphinyDmethyl (bythe method and for the preparation of the correspondingN-cyclopropanecarbonyl derivative) gives O(N',N'-diethylcarbamyl) -N 3,3 -dimethyl allyl) -A -dihydrono roripavine.

O(N,N diethylcarbamyl) N(3,3 dimethylallyl)- A -dihydronororipavine(2.50 g.) is reduced with lithium aluminum hydride by the method usedfor the preparation of the corresponding N-cyclopropylrnethylderivative. Isolation gives crude N(3,3-dimethylallyl)-A-dihydronorori-pavine which is purified by conversion to the salicylatesalt (2.0 g.). A solution of the salicylate salt (1.0 g.) in N-sodiumhydroxide (15 ml.) when saturated with carbon dioxide gives pureN(3,3-dimethylallyl)A -dihydronororipavine base.

Example 9 N(3,3 dimethylallyl) A dihydronororipavine (0.5 g.) whentreated with nicotinoyl chloride in the presence of pyridine (accordingto the method used in the preparation ofN-cyclobutylmethyl-O-nicotinoyLM-dihydro- 2.1 nororipavine) givesN(3,3-dimethallyl)-O-nicotinoyl-A dihydronoro'ripavine which ontreatment with one mole equivalent of hydrobromic acid in methanol at C.gives the hydrobromide salt.

Example N cyclobutylmethyl A dihydronororipavine (0.50 g.) is added to asolution of nicotinoyl chloride hydrochloride (0.52 g.) in dry pyridine(6 ml.). Some heat is evolved and a clear orange solution results. Thissolution is stirred at room temperature for 3 days, after which ether(50 ml.) is added and the ethereal solution washed with saturatedaqueous sodium carbonate (5 20 ml.) and with Water (2X25 ml.), driedover magnesium sulphate, and evaporated, giving the cmde nicotinoylester. A portion of this crude product (0.42 g.) in ethanol (5 ml.) iscooled to 0 C. and stirred while a mixture of 3.734 N-hydrobromic acid(0.20 ml.) and ethanol (5 ml.) is added dropwise. The resulting solutionis diluted with benzene and evaporated under reduced pressure. Theresidue on treatment with ether gives the crude hydrobromide salt of thenicotinoyl ester as a buttcolored solid. Recrystallization from isopropanol gives N cyclobutylmethyl O nicotinoyl A dihydronororipavinehydrobromide as needles, M.P. 254255 C.

Example 11 N-allyldihydronorcodeinone [prepared by the method of Clark,Pessolano, Weijlard, and Pfister, J, Amer. Chem. Soc., 1953, 75, 4963](10.23 g.) is methylated by the same method as that used in thepreparation of N-(cyclopropanecarbonyl)-A -dihydronorthebaine. Afterchromatography on alumina the product is obtained as an oil which oncrystallization from light petroleum gives pure N-allyl-A-dihydronorthebaine as cubes, M.P. 6364 C. A portion of this product(1.60 g.) is dissolved in methanol (80 ml.) and the solution stirred at0 C. while a mixture of 3.734 N-hydrobromic acid (1.305 ml.) andmethanol (20 ml.) is added dropwise. The resulting solution isevaporated at 30 C. under reduced pressure and the residue treated withether, giving the crystalline hydrobromide salt, M.P. 259260 C. (dec.).Recrystallization from ethanol-ether gives N-allyl-h -dihydronorthebainehydrobromide as needles, M.P. 260-261 C. (dec.).

Example 12 N (cyclopropanecarbonyl) O(N',N' diethylcarbamyl)-A-dihydron-ororipavine (4.53 g.) on treatment with methyl hypobromite (bythe method used in the preparation of 7 bromo-Ncyclopropylmethyldihydronorcodeinone dimethyl ketal) gives7-bromo-N-(cyclopropanecarbonyl) O(N',N'diethylcarbamyl)dihydrononmorphinone dimethyl ketal.

7 bromo N (cyclopropanecarbonyl) O(N,N'diethylcarbamyl)dihydronormorphinone dimethyl ketal (1.4 g.) ondehydrobromination (by the method used in the preparation ofnorcodeinone dimethyl ketal) gives N-(cyclopropanecarbonyl) O(N',Ndiethylcarbamyl)normorphinone dimethyl ketal.

N cyclopropanecarbonyl -O(N,N'-diethylcarbamyl) normorphinone dimethylketal (2.4 g.) is dissolved in dry tetrahydrofuran (60 ml.) and thesolution added to a stirred slurry of lithium aluminum hydride (1.2 g.)in dry tetrahydrofuran (60 ml.). The mixture is then stirred underreflux in an atmosphere of nitrogen for 3 hours. At the end of thereaction period the mixture is cooled in ice, and decomposed by additionof a mixture of ethyl acetate 12 ml.) and ether (30 ml.), followed bycautious addition of a solution of disodium dihydrogenethyldiaminetetra-acetate (15 g.) in water (70 ml.). After addition ofbenzene (50 ml.) saturated aqueous sodium bicarbonate is added until theaqueous phase has pH 8. The upper phase is then separated and theaqueous phase extracted with benzene (2x100 ml.). The combined upperphases are dried over magnesium sulphate and 22 evaporated, givingN-cyclopropylmethylnormorphinone dimethyl ketal.

N-cyclopropylmet-hylnormorphinone dimethyl ketal (2.0. g.) is treatedwith anhydrous toluene-p-sulphonic acid in chloroform solution (by themethod used in the preparation of N-cyclopropylmethylnorthebaine). Thecrude reaction product (2.1 g.) is dissolved in dry pyridine(20 ml.) andthe solution cooled to 0 C. and stirred while a mixture of aceticanhydride (4 ml.) and dry pyridine (6 ml.) is added drop wise. Themixture is kept at roomtemperature for 24 hours, then poured intosaturated aqueous sodium bicarbonate ml.). The mixture is extracted withchloroform (3 30 ml.) and the combined chloroform extracts are washedwith saturated aqueous sodium bicarbonate (3x25 ml.), dried overmagnesium sulphate, and evaporated. The residue (2.3 g.) is subjected tochromatography on alumina (45 g.; type H); elution with benzene andevaporation of the eluate gave O-acetyl-N-cyclopropylmethylnororipavine.

A solution of O-acetyl-N-cyclopropylmethylnororipavine (0.70 g.) in 1:3acetone-methanol mixture (100 ml.) is stirred under nitrogen while 2N-sodium hydroxide (10.0 ml.) is added dropwise. Stirring is continuedfor 5 hours at room temperature, after which the reaction mixture isconcentrated under reduced pressure at 30 C. and the aqueous residuediluted with Water (10 ml.) and extracted with ether (3X20 ml.). Theaqueous phase is saturated with carbon dioxide and the resulting mixtureextracted with chloroform (3X25 ml.). The combined chloroform extractsare dried over magnesium sulphate and evaporated, givingN-cyclopropylmethylnororipavine.

A portion (0.3 g.) of the base on treatment with an excess of salicyclicacid in ethanol solution gives N-cyclopropylmethylnororipavinesalicylate.

What is claimed is:

1. A compound selected from the group consisting of a base, its N-oxidederivative and its pharamaceutically acceptable acid addition salts,said base being of the structure:

in which represents an optional carboircarbon bond; R is a memberselected from the group consisting of 1 out-out and in Which R R and Rare members selected from the group consisting of hydrogen, methyl andchloro;

R is methyl; and

R is a member selected from the group consisting of methyl, hydrogen anda lower acyl group derived from a pharmaceutically acceptable carboxylicacid of a maximum of 8 carbon atoms.

2. N-allylnorthebaine.

3. N-cyclopropylmethylnorthebaine.

4. N-cyclopropylmethyl-A -dihydronororipavine.

5. N-cyclopropylmetliyl-A -dihydronororipavine nicotinoate.

6. N-cyclopropylmethyl-A -dihydronorthebaine.

7. N-(3,3-dimethylallyl)-M-dihydronororipavine.

8. N-cyclobutylmethyl-A -dihydronororipavine.

9. N-allyl-A -dihydronorthebaine.

10. The method of preparing A -dihydronorthebaine comprising reactingN-(benzyloxycarbonyl)-A -dihydronorthebaine with triethylsilane in thepresence of triethylamine and palladium chloride to formN-triethylsilyl-A dihydronorthebaine, reacting said N-triethylsilyl-A-dihydronorthebaine with methanol treating the reaction mixture from themethanol treatment with an aqueous citric acid solution to separate theinsoluble acid addition citrate salt and neutralizing said salt to formA -dihydronorthebaine.

11. A chemical compound of the structure I R O OCH References Cited bythe Examiner UNITED STATES PATENTS 2,890,221 6/1959 Rapoport 260-2853,101,339 8/1963 Zeile et al. 260-285 3,153,042 10/1964 Fishman 260285OTHER REFERENCES Bentley: Chemistry of Morphine Alkaloids, Oxford, 1954,pages 69 and relied upon.

Von Braun: Ber. Deut. Chem. volume 59, pages 1081- (1926).

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

HENRY R. JILES, D. G. DAUS, Assistant Examiners.

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A BASE, ITS N-OXIDEDERIVATIVE AND ITS PHARAMACEUTICALLY ACCEPTABLE ACID ADDITION SALTS,SAID BASE BEING OF THE STRUCTURE: 4.N-CYCLOPROPYLMETHYL-$6-DIHYDRONORORIPAVINE.
 14. $6-DIHYDRONORTHEBAINE.